Therapeutically active compounds

ABSTRACT

DISCLOSED HEREIN ARE COMPOUNDS HAVING THE FORMULA   1-(CH3-OOC-),2-(NH2-CH(-R4)-CH(-R)-Z-),(X)N-BENZENE   WHEREIN Z IS OXYGEN OR SULFUR; X IS HYDROGEN, LOWER ALKYL, LOWER ALKOXY, AMINO, DIALKYLAMINO, HALO, LOWER ALKYLTHIO, HYDROXY, CYANO, NITRO OR TRIFLUOROMETHYL; R IS ARYL; R4 IS HYDROGEN OR LOWER ALKYL; AND N IS 1 TO 4; AND ESTERS THEREOF. THESE COMPOUNDS ARE INTERMEDIATES FOR COMPOUNDS WHICH HAVE CENTRAL NERVOUS SYSTEM MODIFYING ACTIVITY.

United States Patent 3,763,214 THERAPEUTICALLY ACTIVE COMPOUNDS JohnKrapcho, Somerset, and Jack Bernstein, New Brunswick, N.J., assignors toE. R. Squibb & Sons, Inc.,

New York, N.Y.

No Drawing. Application May 28, 1970, Ser. No. 50,003, which is adivision of application Ser. No. 533,264, Mar. 10, 1966. Divided andthis application Aug. 7, 1972, Ser. No. 278,504

Int. Cl. C07c 149/40 US. Cl. 260-470 2 Claims ABSTRACT OF THE DISCLOSUREDisclosed herein are compounds having the formula NHz COOGHa wherein Zis oxygen or sulfur; X is hydrogen, lower alkyl, lower alkoxy, amino,dialkylamino, halo, lower alkylthio, hydroxy, cyano, nitro ortrifluoromethyl; R is aryl; R is hydrogen or lower alkyl; and n is 1 to4; and esters thereof. These compounds are intermediates for compoundswhich have central nervous system modifying activity.

RELATED APPLICATIONS and salts thereof, wherein Y is thia (-S), sulfone(SO sulfoxide (SO), and em O-); R is aryl; R is hydrogen, alkyl,haloalkyl, aralkyl, X-substituted aralkyl, allyl, propargyl, cinnamyl,cycloalkylalkylene or AB; R and R are hydrogen or R and R together are0x0 (0:); R is hydrogen or lower alkyl; X is hydrogen lower alkyl loweralkoxy, amino, dialkylamino, halo, lower alkylthio (e.g.,

hydroxy, cyano, nitro or trifluoromethyl; n is l to 4; A is loweralkylene (preferably ethylene and propylene); and B is a basicnitrogen-containing radical of less than twelve carbon atoms. Among thesuitable radicals represented by the symbol B are: amino; (loweralkyl)amino; di(lower alkyl)amino; (hydroxy-lower alkyl)amino; di(hydroXy-lower alkyl)amino; phenyl(lower alkyl)amino; N-(loweralkyl)phenyl (lower alkyl)amino; and saturated 5- to 7-memberedmonocyclic heterocyclic radicals of less than twelve carbon atoms, asexemplified by piper-idino; (lower alkyl)piperidino; di(loweralkyl)piperidino; (lower alkoxy)piperidino; homopiperidino; 2,3- or 4-piperidyl; 2,3- or 4-(N-lower alkylpiperidyl); pyrrolidino;

3,763,214 Patented Oct. 2, 1973 (lower alkyl)pyrrolidino; di(loweralkyl)pyrrolidino; (lower alkoxy)pyrrolidino; 2- or 3-pyrrolidyl; 2- or3-(N- lower alkyl pyrrolidyl); morpholino; (lower alkyl) morpholino;di(lower alkyl)morpholino; (lower alkoxy) morphoino; thiarnorpholino;(lower alkyl)thiamorpholino; di(lower alkyl)thiamorpholino; (loweralkoxy)thiamorpholino; piperazino; 4-R -substituted piperazino (e.g., N-ethylpiperazino); [hydroXy-(lower alkyl)]piperazino [e.g., N-(Z-hydroxyethyl)piperazino]; (lower alkyl) piperazino (e.g., N-methylpiperazino); di(lower alkyl) piperazino; (loweralkoxy)piperazino; homopiperazino; and 4-R -substituted homopiperazino(e.g., N -benzylhomopiperazino). The terms lower alkyl, lower alkoxy,and lower alkylene, as employed herein, includes both straight andbranched chain radicals of less than eight carbon atoms. The term arylas employed herein includes mononuclear and dinuclear radicals such asX-substituted phenyl (including 3,4-methylenedioxyphenyl and3,4-ethylenedioxyphenyl), furyl, thienyl, naphthyl or pyridyl. Theparticularly preferred compounds are those wherein X is hydrogen, Y issulfur, R is phenyl, R is AB, wherein A is ethylene and N isdimethylamino and R and R together is oxo.

As to the salts, those coming within the purview of this inventioninclude the acid-addition salts of those compounds containing a basicgroup (e.g., wherein R is --AB or R and R are both hydrogen)particularly the non-toxic acid-addition salts and the quaternaryammonium salts. Acid useful for preparing these acid-addition saltsinclude, inter alia, inorganic acids, such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acid, sulfuric acid, nitric acid,and phosphoric acid, and organic acids such as maleic, tartaric citric,acetic, salicyclic, succinic acid, theophylline 8-chloroetheophylline,maleic, benzoic, nicotinic, methanesulfonic or cyclohexanesulfamic. Thequaternary ammonium salts include those formed with lower alkyl halides(e.g., methyl bromide, ethyl chloride and propyl iodide), benzyl halides(e.g., benzyl chloride) and dilower alkyl sulfates (e.g., dimethylsulfate).

Compounds of this invention and the salts thereof possess centralnervous system modifying activity, particularly as depressants and aretherefore useful as tranquilizers. They may be administered orally orparenterally in the form of tablets, capsules, elixirs, injectables, orthe like, by incorporating the appropriate dosage of the compound ofFormula I or a physiologically acceptable salt thereof in a dosage rangesimilar to that used with chlorodiazepoxide.

The compounds of this invention may be prepared by the following novelprocess. Thiosalicylic acid, salicylic acid or an X-substitutedderivative thereof is condensed with a nitro-compound having a FormulaII wherein R and R are as defined hereinabove. This condensation yieldsa product having Formula III wherein Z is oxa or thia and R and R are asdefined above. The acid group is converted to an ester (e.g., methylester) and then treated with a reducing agent. Any reducing agent may beutilized in the practice of this invention such as iron-acetic acid,tin-hydrochloric acid, with the preferred reducting agent being stannouschloride.

The product formed has the Formula IV:

COOCH;

wherein X, R, R and n are as hereinabove described. Compound IV isheated to form the novel intermediate ring Compound V:

Alternately, Compound V may be prepared by treating Compound III withstannous chloride and the resulting amino acid heated in the same manneras utilized in the conversion of Compound IV to Compound V. Compound Vis then condensed with an aminoalkyl halide of the formula BAY or R Ywherein B, A and R are as hereinbefore defined and Y is halide, e.g.,bromine, chlorine, and so forth, to give Compound I. This reaction ispreferably conducted by heating the reactants in the presence of a basiccondensing agent, such as an alkali metal, an alkali metal amine (e.g.,sodamide), or an alkali metal hydroxide. In some cases where R is -A--Bin Compound I, it is preferred to react Compound V with Y -AY to give acompound where R =A--Y This material is then heated with H-B in an inertsolvent as benzene or toluene. To form the acid-addition salts or thequaternary ammonium salts, the free base initial- 1y formed isinteracted with at least one equivalent of the desired acid orquaternary ammonium hydrocarbon halide.

Suitable derivatives of thiosalicylic and salicylic acid are:

3-butyl-Z-marcaptobenzoic acid; 4-octyI-Z-mercaptobenzoic acid;3-methyl-5-butyl-2-mercaptobenzoic acid; 3-isobutoxy-2-mercaptobenzoicacid; 6-methyl-Z-mercaptobenzoic acid;S-amino-3-heptyl-2-mercaptobenzoic acid; 3,5-dichloro-2-mercaptobenzoicacid; 3,4,5,6-tetrafluoro-Z-mercaptobenzoic acid;4-phenylthio-Z-mercaptobenzoic acid; S-trifiuoromethyl-Z-mercaptobenzoicacid; 4-isopropyl-2-hydroxybenzoic acid;3,4,5,6-tetramethyl-2-hydroxybenzoic acid;3-methyl-5-butyl-2-hydroxybenzoic acid; 4-isobutoxy-Z-hydroxybenzoicacid; 4-cyano-2-hydroxybenzoic acid; 6-pentoxy-Z-hydroxybenzoic acid;3-bromo-2-hydroxybenzoic acid.

The reactants of Formula II may be prepared by the reacting of analdehyde having the formula R-CHO with a nitroalkane of the formula R-CH -NO wherein R and R are defined above. Examples of compound H are 1-(3 ,4-dichlorophenyl -2-nitroethane;

1- (2,3 ,4,5,6-p entafluorophenyl) -2-nitroethene;

1- 2,6-dichloro-3-methoxyphenyl) -2-nitrobutene; 1- 2-furyl)-2-nitroethene;

1- (Z-tihophene) -2-nitroethene;

1- (2-pyridyl) -2-nitroethene 1-(3,4-dimethylpheny1)-2-nitroethene;

4 1- 2,5 -dioctylphenyl -2-nitrobutene; 1- (2-hydroxyphenyl)-2-nitrobutene; 1- (4-isopropoxyphenyl -2-nitrobutene; and so forth.

Compound I wherein R and R together is oxo (0:) may be reduced as bytreatment with a reducing agent such as lithium aluminum hydride in anorganic solvent such as ether or tetrahydrofuran to give the compoundwherein R and R are hydrogen.

The nitro-derivatives of the instant invention, wherein X is nitro, maybe prepared by reacting compound V with fuming nitric acid. The productrecovered may then be reduced to form an amino derivative. The hydroxyderivative of compound V may be formed by reacting a compound wherein Xis alkoxy with concentrated bydrochloric acid or with pyridinehydrochloride. Final product V may be converted to its correspondingsulfone and sulfoxide derivatives by oxidation. Compound V may bereacted with hydrogen peroxide to yield the sulfoxides while if it isreacted with potassium permanganate, the sulfones will be produced.

The following examples illustrate the invention, all temperatures are indegrees centigrade unless otherwise stated:

EXAMPLE 1 3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-5-one (A)Preparation of 2-[ [a- (nitromethyl)benzyl] thio] benzoic acid: Amixture of g. of thiosalicylic acid, 100 g. of w-nitrostyrene and 300m1. of ethanol is heated; the resulting solution refluxed for threehours, diluted with 15 ml. of water and cooled to give 160.3 g. ofcolorless crystalline product, M.P. ISO-152.

(B) Preparation of 2-[[ot-(nitromethyl)benzyl]t-hio] benzoic acid,methyl ester: A suspension of 141 g. of the material from part A in 300ml. of chloroform is treated with 300 ml. of thionyl chloride andthemixture refluxed for three hours. The mixture is then concentrated untilabout 350 ml. of distillate is collected and the residue evaporatedunder reduced pressure to give 157 g. of the nearly colorless acidchloride, M.P. 89-91". This material is treated with 600 ml. ofmethanol, heated and the resulting solution refluxed for three hours.Cooling this solution gives 141.1 g. of colorless prouct, M.P. 99-101".

(C) Preparation of 2-[[a-(aminomethyl)benzyl]thio] benzoic acid, methylester: A mixture of 130 g. of the material from part B, 350 g. ofstannous chloride dihydrate and 1 1. of methanol is treated with 300 ml.of acetic acid, refluxed for three hours and then distilled until 500ml. of solvent is collected. The residue is cooled and poured onto acold mixture of a solution of 700 g. of potassium carbonate in 1 l. ofWater, 200 ml. of chloroform and 600 ml. of ether. The mixture isshaken, the organic layer separated and the aqueous phase is extractedtwice With a mixture of 200 ml. chloroform-600 ml. ether. The organicphases are combined, dried over magnesium sulfate, treated with Darco,filtered and concentrated under reduced pressure to give g. of residue.This material is dissolved in 700 ml. of dry ether, decanted from thesmall quantity of insoluble material and the solution treated with 300ml. of ether containing 45 ml. of 7.7 N alcoholic hydrogen chloride togive a hydrochloride salt which separates as an oil. The mother liquoris decanted from the oil and the latter placed under reduced pressure togive 98.5 g. of a foam-like solid. The latter is suspended in 500 ml. ofether, treated with 100 ml. of water and a solution of 45 g. ofpotassium carbonate in 80 ml. of Water. The mixture is shaken, theorganic phase is separated and the aqueous phase extracted twice with300 ml. of ether. The organic phases are combined, dried over magnesiumsulfate, treated with Darco, filtered and concentrated under reducedpressure to give 83.7 g. of product, a pale brown syrup. The ethyl,butyl, isobutyl, heptyl and octyl esters may be prepared in a likemanner by utilizing the appropriate alcohol in lieu of methanol in theabove example.

(D) Preparation of 3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-S-one:

Method A.--A solution of 83.7 g. of material from part C in 900 m1. ofxylene is refluxed for 8.5 hours; the mixture is then concentrated until500 ml. of distillate is collected and the residue cooled to give 23.3g. of nearly colorless solid, M.P. 180-182". After recrystallizationfrom ethanol, the colorless product melts at 183-185.

Method B.A sample of material from part C (20.0 g.) is placed in 100 ml.flask and slowly heated and distilled (about 180-220 at 0.2 mm.) to give15.9 g. of distillate. The latter is crystallized from 30 ml. of tolueneto give 7.2 g. of colorless solid, M.P. 182-185 EXAMPLE 24-(2-dimthylaminoethyl)-3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-S-one, hydrochloride To a suspension of 1.4 g. ofsodamide in 150 ml. of toluene is added 9.0 g. of the material from partD of Example 1 and the mixture heated to 60 to obtain a clear solution.The solution is cooled to 25, treated with 45 ml. of 1.1 N toluenesolution of 2-dimethylarninoethyl bromide and then heated at 50-70 forfive hours. The mixture is cooled to room temperature, treated with 75ml. of water and the layers are separated. The organic phase isextracted with a solution of 5 ml. of concentrated hyrochloric acid in100 m1. of water. This aqueous phase is cooled and treated with asolution of g. of potassium carbonate in ml. of Water to give an oilyproduct which is extracted with three 100 ml. portions of ether. Theether phases are combined, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give 5.6 g. of solid, M.P.123-125". After trituration with 50 ml. of hexane, the colorless productweighs 5.2 g., M.P. 125-127". A solution of 5.0 g. of this base in ml.of ethanol is treated with 2.0 ml. of 7.7 N alcoholic hydrogen chloride;the hydrochloride salt rapidly crystallizes and the mixture is dilutedwith 50 ml. of ether to give 5.4 g. of product, M.P. 266-268". Afterrecrystallization from 180 ml. of hot ethanol, the colorless materialweighs 4.5 g., M.P. 271-273.

This material is a mixture of d and l isomers. By treatment of the freebase with an equivalent quantity of an optically active acid, such asd-tartaric acid, the isomers can be separated by differences of theirsolubility in organic solvents.

EXAMPLE 3 4-(diethylaminoethyl)-3,4-dihydro-2-phenyl-2H-l,4-benzothiazepin-S-one, hydrochloride A suspension of 1.8 g. of sodamidein 300 ml. of toluene is treated with 11.3 g. of material from part D ofExample 1 and the mixture heated to 60. The resulting solution istreated with 25 ml. of a 2.2 N toluene solution of 2- diethylaminoethylchloride and then heated to 60-70 for three hours, followed by heatingto reflux for a period of two hours. After cooling the reaction productis isolated according to the procedure used in Example 2 to give 14.5 g.of base as a syrupy oil. This material is dissolved in 300 ml. of ether,washed with 10 ml. of water (three times), dried over magnesium sulfate,filtered and concentrated under reduced pressure to give 12.3 g. ofbase. A solution of this material in 25 ml. of ethanol is treated with4.5 ml. of 7.7 N alcoholic hydrogen chloride and the resulting solutiondiluted to 100 ml. with ether to give 11.7 g. of pale yellow solid, M.P.194-197. This material is digested in ml. of hot acetonitrile, cooledand filtered to give 10.4 g. of colorless product, M.P. 213-215Recrystallization from 35 ml. ethanol gives 9.0 g. of crystallineproduct, M.P. 213-215 EXAMPLE 43,4-dihydro-4-[3-(4-methyl-l-piperazinyl)propyl1-2-phenyl-ZH-1,4-benzothiazepin-5-one, dihydrochloride Asuspension of 7.0 g. of material from part D of Example 1 in ml. oftoluene is stirred and treated with 4.4 g. of powdered sodium hydroxide.This mixture is stirred for five minutes, treated with 14 g. of finelydivided 1-(3 bromo-propyl)-4-methylpiperazine dihydrobromide and thenheated on a steam bath for forty-five minutes. The mixture is cooled,treated with 50 m1. of water and and filtered. The aqueous phase isdiscarded and the product extracted from the organic phase in the mannerdescribed in Example 2 to give 2.5 g. of base. A solution of thismaterial in 10 ml. of ethanol is treated with 2 ml. of 7.7 N alcoholichydrochloride to give a crystalline mass. After dilution with 50 ml. ofether, the product is filtered to give 2.7 g. of product, M.P. 260-262".Recrystallization from 60 ml. of methanol gives 1.9 g. of colorlessproduct, M.P. 265-267".

EXAMPLE 5 2,3,4,5-tetrahydro-2-phenyl-1,4-benzothiazepine, hydrochlorideTo a suspension of 2.2 g. of lithium aluminum hydride in 600 ml. ofether is added 6.4 g. of the material from Example 1. The mixture istreated with 300 ml. of toluene, stirred, refluxed for nine hours,cooled and treated dropwise with 10 ml. of water and then with asolution of 2 g. of sodium hydroxide in 10 ml. of water. After stirringthe mixture for two hours, the insoluble material is filtered and washedwith ether. The filtrate is dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give 5.5 g. of an oily residue.The latter is dissolved in 40 ml. of ethanol and treated with 3 ml. of7.7 N alcoholic hydrogen chloride. The hydrochloride salt, rapidlycrystallized, is then diluted with 40 ml. of ether and filtered to give4.9 g. of nearly colorless solid, M.P. 273- 275. After crystallizationfrom 330 ml. of ethanol, the colorless product weighs 3.8 g., M.P.275-277.

EXAMPLE 6 4- Z-dimethylaminoethyl) -2,3,4,5-tetrahydro-2-phenyl-1,4-benzothiazepine, hydrochloride Following the procedure utilized inExample 5 but substituting an equivalent quantity of the free base ofExample 2 for 3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-5- one theproduct formed is 4-(2-dimethylaminoethyl)-2,3,4,5-tetrahydro-2-phenyl-1,4-benbothiazepine, hydrochloride.

EXAMPLE 7 4- [2-( l-pyrrolidinyl ethyl] -3,4-dihydro-2-phenyl-2H- l ,4-benzothiazepin-S-one, hydrochloride Following the procedure utilized inExample 2 but substituting an equivalent amount of2-(1-pyrrolidinyl)ethyl chloride for the Z-dimethylaminoethyl bromidethe product formed is 4-[2-(1-pyrrolidinyl)ethyl] 3,4 dihydro-2-phenyl-2H-1,4-benzothiazepin-5-one, hydrochloride.

EXAMPLE 8 4-(3-dimethylaminopropyl)-3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-S-one, hydrochloride Following the procedure utilized inExample 2 but substituting an equivalent amount of 3-dimethylaminopropylbromide for the Z-dimethylaminoethyl bromide the product formed is4-(3-dimethylaminopropyl)-3,4-dihydro-2-phenyl-ZH-1,4-benzothiazepin-5-one, hydrochloride.

EXAMPLE 9 4- [2- (N-methyl-N-phenethylamino) ethyl] -3 ,4-dihydro-2-phenyl-ZH-1,4-benzothiazepin-5-one, hydrochloride Following theprocedure utilized in Example 2 but substituting an equivalent amount ofZ-(N-methyl-N-phen- 7 ethylamino)ethyl chloride for the2-dimethylaminoethyl bromide the product formed is4-[2-(N-methyl-N-phenethylamino)ethyl-3,4-dihydro 2 phenyl2H-l,4-benzothiazepin-S-one, hydrochloride.

EXAMPLE 10 4-(2-morpholinoethyl) -3,4+dihydro-2-phenyl-2H-1,4-

benzothiazepin-S-one, hydrochloride Following the procedure utilized inExample 2 but substituting an equivalent amount of 2-morpholinoethylchloride for the Z-dimethylaminoethyl bromide the product formed is4-(2-morpholinoethl) 3,4 dihydro-2-phenyl- 2H-,1,4-benzothiazepin-5-one,hydrochloride.

EXAMPLE 1 1 7-methoxy-3,4-dihydro-2-furyl-2H-1,4- benzoxazepin-S-oneFollowing the procedure utilized in Example 1 but substitutingS-methoxy-Z-hydroxybenzoic acid in lieu of thiosalicylic acid and1-(2-furyl) 2 nitroethene in lieu of w-nitrostyrene the product formedis 7-methoxy-3,4-dihydro-2-furyl-2H-1,4-benzoxazepin-5-one.

EXAMPLE l2 4-(2-dimethylaminoethyl)-8-nitro-3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-5-one 4-(2-dimethylaminoethyl 3,4 dihydro 2phenyl- 2H-1,4-benzothiazepin-5-one of Example 2 is reacted with coldfuming nitric acid and the mixture poured onto ice-Water. The productrecovered is 4-(2-dimethylaminoethyl) 8 nitro 3,4dihydro-Z-phenyl-ZH-1,4-benzothiazepin-S-one.

EXAMPLE l3 4-(Z-dimethylaminoethyl)-3,4-dihydro-2phenyl-2H-1,4-benzothiazepin-S-one, l-oxide To a solution of hydrogen peroxide 4-(2dimethylaminoethyl) 3,4 dihydro 2 phenyl-2H-l,4-benzothiazepin-S-one isadded and the product recovered is 4-(2-dimethylaminoethyl) 3,4dihydro2-phenyl-2H-l, 4-benzothiazepin-5-one, l-oxide.

EXAMPLE 14 4-(Z-dimethylaminoethyl)-3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-S-one, 1,1-dioxide Repeating the procedure of Example 11but utilizing potassium permanganate in lieu of hydrogen peroxide theproduct recovered is4-(2-dimethylaminoethyl)-3,4-dihydro-2-phenyl-2H-l,4-benzothiazepin-5-one,1,1-dioxide.

EXAMPLE 15 2- (p-chlorophenyl)-3,4-dihydro-3-ethyl-2H-1,4-benzothiazepin-S-one Following the procedure utilized in Example 1 butsubstituting an equivalent quantity of l-(p-chlorophenyl)-2- nitrobutenefor the w-nitrostyrene the product formed is 2-(p-chlorophenyl) 3,4dihydro 3 ethyl-2H-l,4 benzothiazepin-S-one.

EXAMPLE l6 3,4-dihydro-4-methyl-2-phenyl-2H-l,4-

' benzothiazepin-S-one Following the procedure utilized inExample 3 butsubstituting an equivalent quantity of dimethyl sulfate for the2-diethylaminoethyl chloride the product formed is3,4-dihydro-4-methyl-2-phenyl 2H 1,4 benzothiazepin- -one.

EXAMPLE l7 4 (3-chloropropyl)-3,4-dihydro-2-phenyl-2H-1,4-

benzothiazepin-S-one Following the procedure utilized in Example 2 butsubstituting an equivalent quantity of l-bromo-3-chloropropane for theZ-dimethylaminoethyl bromide the product formed is 4-(3-chloropropyl)3,4 dihydro 2 phenyl- 2H-1,4-benzothiazepin-5-one.

EXAMPLE 18 3,4-dihydro-4-[3-(4-B-hydroxyethyl l piperazinyl)propyl] 2phenyl-2H-1,4-benzothiazepiu-5-one, hydrochloride A solution ofequivalent quantities of the material from Example 17 and l-3-hydroxyethylpiperazine in toluene is heated and refluxed for two hoursand the solvent removed under reduced pressure is give 3,4-dihydro-4-[3-(4-fl-hydroxyethyl) 1 piperazinyl)propyl] 2 phenyl-2H-1,4-benzothiazepin-5-one, hydrochloride.

EXAMPLE 19 3,4-dihydro-2-(5-ethyl-2-pyridyl)-2H-1,4-benzothiazepin-S-oneFollowing the procedure utilized in Example 1 but substituting anequivalent amount of l-(5-ethyl-2-pyridyl)-2- nitroethene for thew-nitrostyrene the product formed is 3,4-dihydro-2-(5-ethyl-2-pyridyl)2H 1,4 benzothiazepin-S-one.

EXAMPLE 20 4( 2-dimethylaminoethyl)-3,4-dihydro-2-phenyl-2H-1,4-benzothiazepin-S-one, methochloride A solution of 5.0 g. of the freebase of the material from Example 2 in 50 ml. of acetonitrile is cooledand treated with 15 g. of methyl chloride. The solution is allowed tostand for a day at room temperature and the solvent removed underreduced pressure to give 4-(2-dimethylaminoethyl 3,4 dihydro e 2phenyl-2H-l,4- benzothiazepin-S-one, methochloride.

EXAMPLE 21 (X n I OOOCH NH;

wherein Z is sulfur; X is hydrogen, trifiuoromethyl; R is phenyl; R isalkyl; and n is 1 to 4.

2. A compound of claim 1 which is 2-[[a-(aminomethyl)benzyl]thio1-benzoic acid, methyl ester.

lower alkyl, halo, or hydrogen or lower References Cited UNITED STATESPATENTS 3,105,090 9/1963 Leonard 26047O LORRAINE A. WEINBERGER, PrimaryExaminer J. F. TERAPANE, Assistant Examiner US. Cl. X.R. 260-516 3 3UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 7 1 Dt d October 2, 1973 Inventofls) John Krapcho et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 56, insert a comma after the words "hydrogen" and"alkyl".

Column 2, line 29, "Acid" should read -Acids-.

Column 3, line 1, "reducting" should read --reducing-.

Column 3 line 29, delete the after "B-A-Y Column 3, line 34, "amine"should read -amide-. Column 3, line 54, "phenylthio" should readpentylthio-'-. Column 3, line 59, isobutoxy" should; read --isobutoxyl-.

Column 3, line 73, "tihophene" should read -thiophene.

Column 5, line 18, "dimthylaminoethyl" should read --dimethylaminoethyl.

Column e 9. "benbothiazepine" sh l read a -benzothiazepine-- Column 7,line I 12, "morpholinoethl" should read .morpholino' ethyl-.

Signed and sealed this 19th day of February 197L;..

(SEAL) Attest: r u ,l, M

EDWARD MELETCHERJR. 'C. MARSHALL DANN At testing Officer Commissioner ofPatents

